ABSTRACT Alzheimer?s disease (AD) is the most common form of dementia in the United States, affecting over 5 million Americans. Unfortunately, there are currently no effective therapeutic strategies to slow, halt, or reverse the advance of the disease. As a noninvasive procedure, Low-level Laser Therapy (LLLT) or photobiomodulation is widely practiced to stimulate healing, relieve pain, and reduce inflammation. Our previous studies on AD animal models and our preliminary data on a novel and clinically relevant transgenic rat model have shown that LLLT can strongly protect against AD pathological hallmarks and cognitive decline. This exciting observation has led to hope that further studies of LLLT neuroprotection against AD could potentially lead to new therapies in humans. The overall goal of the current proposal is to test the neuroprotective and cognitive improvement effects of LLLT on AD pathology, and to elucidate the underlying mechanisms. We hypothesize that leakage of blood hemoglobin (blood-Hb) into brain tissue through the compromised blood brain barrier (BBB) during AD progression aggregates A? plague formation, enhances oxidative stress and inflammation, and accelerates tauopathy. Alongside this, AD-induced mitochondrial fragmentation and energy depletion, as well as decreases in neuronal hemoglobin (Neu-Hb), weakens cellular resistance to A? toxicity. Collectively, AD induces extracellular A? deposits, aberrant intracellular mitochondrial fission and dysfunction, neurofibrillary tangles, and oxidative and inflammatory damage that ultimately culminate in neurodegeneration and cognitive decline. However, we hypothesize that LLLT can confer neuroprotective and cognitive benefits in AD pathology. We posit that these benefits result from LLLT?s ability to preserve healthy mitochondrial fission/fusion dynamics, thereby promoting mitochondrial function as well as enhancing endogenous heme biosynthesis. In addition, we propose that LLLT induced shifts in mitochondrial dynamics will potentiate nuclear translocation of HIF-1? to induce the target gene expression. On the one hand, the induced factors are able to protect and repair BBB damage, thereby reducing A? aggregation exacerbated by exogenous blood-Hb. On the other hand, HIF-1?-induced globin can be assembled with mitochondrial-produced heme to form Neu-Hb to exert beneficial effects. The proposed studies would advance the field by determining the potential efficacy of LLLT for protection of the AD brain. Specific Aim 1 would test the hypothesis that LLLT exerts neuroprotection and improves functional outcome in transgenic AD rats. Specific Aim 2 would test the hypothesis that preservation of mitochondrial dynamics and restoration of mitochondrial function underlies LLLT?s neuroprotective abilities. Specific Aim 3 would test the hypothesis that LLLT reduces A? aggregation and increases neuronal resistance/homeostasis via the activation of Mitochondria-HIF-1?-Hb pathway in AD pathological conditions.